Determining a quantity of an analyte in a blood sample

ABSTRACT

A medical system for determining an analyte quantity in a blood sample via a cartridge that spins around a rotational axis. The cartridge may include: a separation chamber that separates blood plasma from the sample; a processing chamber containing a reagent with a specific binding partner which binds to the analyte to form an analyte specific binding partner complex; a first valve structure connecting the separation chamber to the processing chamber; a measurement structure to measure the quantity of the analyte, wherein the measurement structure includes a chromatographic membrane with an immobilized binding partner for direct or indirect binding of the analyte or the analyte specific binding partner complex, and an absorbent structure that is nearer to the axis than the membrane; a second valve structure connecting the processing chamber to the measurement structure; and a fluid chamber filled with a washing buffer and fluidically connected to the measurement structure.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of international Application No.PCT/EP2016/078916, filed Nov. 25, 2016, which claims priority toEuropean Application No. 15196519.1, filed Nov. 26, 2015. Theseapplications, in their entirety, are incorporated herein by reference.

TECHNICAL FIELD

This application relates to analytical test devices for biologicalsamples, and in particular to the design and use of rotatable cartridgesfor performing a measurement of a blood sample.

BACKGROUND

Two classes of analysis systems are known in the field of medicalanalysis: wet analysis systems, and dry-chemical analysis systems. Wetanalysis systems, which essentially operate using “wet reagents” (liquidreagents), perform an analysis via a number of required step such as,for example, providing a sample and a reagent into a reagent vessel,mixing the sample and reagent together in the reagent vessel, andmeasuring and analyzing the mixture for a measurement variablecharacteristic to provide a desired analytical result (analysis result).Such steps are often performed using technically complex, large,line-operated analysis instruments, which allow manifold movements ofparticipating elements. This class of analysis system is typically usedin large medical-analytic laboratories.

On the other hand, dry-chemical analysis systems operate using “dryreagents” which are typically integrated in a test element andimplemented as a “test strip”, for example. When these dry-chemicalanalysis systems are used, the liquid sample dissolves the reagents inthe test element, and the reaction of sample and dissolved reagentresults in a change of a measurement variable, which can be measured onthe test element itself. Above all, optically analyzable (in particularcolorimetric) analysis systems are typical in this class, in which themeasurement variable is a color change or other optically measurablevariable. Electrochemical systems are also typical in this class, inwhich an electrical measurement variable characteristic for theanalysis, in particular an electrical current upon application of adefined voltage, can be measured in a measuring zone of the test elementusing electrodes provided in the measuring zone.

The analysis instruments of the dry-chemical analysis systems areusually compact, and some of them are portable and battery-operated. Thesystems are used for decentralized analysis (also called point-of-caretesting), for example, at resident physicians, on the wards of thehospitals, and in so-called “home monitoring” during the monitoring ofmedical-analytic parameters by the patient himself (in particular bloodglucose analysis by diabetics or coagulation status by warfarinpatients).

In wet analysis systems, the high-performance analysis instruments allowthe performance of more complex multistep reaction sequences (“testprotocols”). For example, immunochemical analyses often require amultistep reaction sequence, in which a “bound/free separation”(hereafter “b/f separation”), i.e., a separation of a bound phase and afree phase, is necessary. According to one test protocol, for example,the sample can first be brought in contact with a specific bindingreagent for the analyte which is immobilized onto a surface. This can beachieved for example by mixing the sample with beads comprising surfaceswith such immobilized reagents or transporting the sample over surfacesor through porous matrices wherein the surfaces or the porous matricescomprise coatings of the immobilized reagents. A marking reagent cansubsequently be brought in contact with this surface in a similar mannerto mark the bound analyte and allow its detection. To achieve a moreprecise analysis, a subsequent washing step is often performed, in whichunbound marking reagent is at least partially removed. Numerous testprotocols are known for determining manifold analytes, which differ inmanifold ways, but which share the feature that they require complexhandling having multiple reaction steps, in particular also a b/fseparation possibly being necessary.

Test strips and similar analysis elements normally do not allowcontrolled multistep reaction sequences. Test elements similar to teststrips are known, which allow further functions, such as the separationof red blood cells from whole blood, in addition to supplying reagentsin dried form. However, they normally do not allow precise control ofthe time sequence of individual reaction steps. Wet-chemical laboratorysystems offer these capabilities, but are too large, too costly, and toocomplex to handle for many applications.

To close these gaps, analysis systems have been suggested which operateusing test elements which are implemented in such a manner that at leastone externally controlled (i.e., using an element outside the testelement itself) liquid transport step occurs therein (“controllable testelements”). The external control can be based on the application ofpressure differences (overpressure or low-pressure) or on the change offorce actions (e.g., change of the action direction of gravity byattitude change of the test element or by acceleration forces). Theexternal control can be performed by centrifugal forces, which act on arotating test element as a function of the velocity of the rotation.

Analysis systems having controllable test elements are known andtypically have a housing, which comprises a dimensionally-stable plasticmaterial, and a sample analysis channel enclosed by the housing, whichoften comprises a sequence of multiple channel sections and chambersexpanded in comparison to the channel sections lying between them. Thestructure of the sample analysis channel having its channel sections andchambers is defined by profiling of the plastic parts. This profiling isable to be generated by injection molding techniques or hot stamping.However, microstructures, which are generated by lithography methods,are increasingly being used more recently.

Analysis systems having controllable test elements allow theminiaturization of tests which have only been able to be performed usinglarge laboratory systems. In addition, they allow the parallelization ofprocedures by repeated application of identical structures for theparallel processing of similar analyses from one sample and/or identicalanalyses from different samples. It is a further advantage that the testelements can typically be produced using established production methodsand that they can also be measured and analyzed using known analysismethods. Known methods and products can also be employed in the chemicaland biochemical components of such test elements.

In spite of these advantages, there is a further need for improvement.In particular, analysis systems which operate using controllable testelements are still too large. The most compact dimensions possible areof great practical significance for many intended applications.

United States patent application US 2009/0191643 A1 describes a testelement and method for detecting an analyte with the aid thereof isprovided. The test element is essentially disk-shaped and flat, and canbe rotated about a preferably central axis which is perpendicular to theplane of the disk-shaped test element. The test element has a sampleapplication opening for applying a liquid sample, a capillary-activezone, in particular a porous, absorbent matrix, having a first end thatis remote from the axis and a second end that is near to the axis, and asample channel which extends from an area near to the axis to the firstend of the capillary-active zone that is remote from the axis.

U.S. Pat. No. 8,759,081 B2 discloses a test element, analytical systemand method for optical analysis of fluid samples is provided. The testelement has a substrate and a microfluidic channel structure, which isenclosed by the substrate and a cover layer. The channel structure has ameasuring chamber with an inlet opening. The test element has a firstlevel, which faces the cover layer, and a second level, whichinterconnects with the first level such that the first level ispositioned between the cover layer and the second level. A part of themeasuring chamber extending through the first level forms a measuringzone connecting with a part of the measuring chamber that extendspartially into the second level, forming a mixing zone. Optical analysisof fluid samples is carried out by light guided through the first levelparallel to the cover layer, such that the light traverses the measuringzone along an optical axis.

U.S. Pat. No. 8,911,684 B2 discloses a microfluidic element foranalyzing a bodily fluid sample for an analyte contained therein isprovided, the element having a substrate, a channel structure that isenclosed by the substrate, and a cover layer, and is rotatable around arotational axis. The channel structure of the microfluidic elementincludes a feed channel having a feed opening, a ventilation channelhaving a ventilation opening, and at least two reagent chambers. Thereagent chambers are connected to one another via two connectionchannels in such a manner that a fluid exchange is possible between thereagent chambers, one of the reagent chambers having an inlet opening,which has a fluid connection to the feed channel, so that a liquidsample can flow into the rotational-axis-distal reagent chamber. Atleast one of the reagent chambers contains a reagent, which reacts withthe liquid sample.

SUMMARY

The present application discloses herein a method and a medical systemin the independent claims. Embodiments are given in the dependentclaims.

A cartridge as used here encompasses also any test element forprocessing a biological sample into a processed biological sample. Thecartridge may include structures or components which enable ameasurement to be performed on the biological sample. A typicalcartridge is a test element as is defined and explained in U.S. Pat. No.8,114,351 B2 and US 2009/0191643 A1. A cartridge as used herein may alsobe referred to as a Centrifugal microfluidic disc, also known as“lab-on-a-disc”, lab-disk or a microfluidic CD.

A biological sample as used herein encompasses as chemical productderived, copied, replicated, or reproduced from a sample taken from anorganism. A blood sample is an example of a biological sample that iseither whole blood or a blood product. The blood plasma may beconsidered to be a processed biological sample.

It is understood that references to blood samples and products below andin the claims may be modified such that they refer to biologicalsamples.

In one aspect, an embodiment of the invention provides for a method ofdetermining a quantity of an analyte in a blood sample using acartridge. A quantity as used herein may refer to an absolute quantity(amount) of an analyte that is measured within the sample and may begiven in units like gram or mol. In some examples the absolute quantityof an analyte may be calibrated to the amount of solvent (weight orvolume) and will result in a concentration of the analyte in the bloodsample given in units like gram/ml or mol/l. As such the term quantityin the claims and/or disclosure may be replaced with the term“concentration.”

The cartridge is operable for being spun around a rotational axis. Thecartridge comprises an inlet for receiving a blood sample. The cartridgefurther comprises a blood separation chamber for separating blood plasmafrom the corpuscular blood sample components by centrifugation. TheUnited States Patent 2009/0191643 A1 illustrates a microfluidicstructure in a rotational disc that is able to separate serum or plasmafrom the blood cell fraction (mainly the erythrocytes) of a whole bloodsample.

The cartridge further comprises a processing chamber containing at leastone reagent. The at least one reagent comprises at least one specificbinding partner which is operable to bind with the analyte to form atleast one analyte-specific binding partner complex. The cartridgefurther comprises a first valve structure connecting the bloodseparation chamber to the processing chamber. The cartridge furthercomprises a measurement structure for enabling the measurement of thequantity of an analyte. The measurement structure comprises achromatographic membrane. The chromatographic membrane comprises animmobilized binding partner for direct or indirect binding of theanalyte or the at least one analyte-specific binding partner complex.The measurement structure further comprises an absorbent structure. Theabsorbent structure is nearer to the rotational axis than the membrane.The absorbent structure may support the complete transport of theprocessed fluid across or through the chromatographic membrane and mayalso serve as a waste-fleece by binding the processed fluids and/oradditional fluids like washing buffers, thus avoiding their leakage andthereby contamination of the instrument or user.

The cartridge further comprises a second valve structure connecting theprocessing chamber to the measurement structure. The cartridge furthercomprises a fluid chamber filled with a washing buffer. The fluidchamber is fluidically connected to the measurement structure. A sealkeeps the washing buffer within the fluid chamber.

The method comprises placing the blood sample into the inlet. The methodfurther comprises rotating the cartridge about the rotational axis totransport the blood sample into the blood separation chamber. The methodfurther comprises controlling the rotation of the cartridge about therotational axis to separate the blood plasma from the corpuscular bloodsample components by centrifugation. The method further comprisesopening the first valve structure and rotating the cartridge about therotational axis to transport a defined portion of the blood plasma fromthe blood separation chamber to the processing chamber. In differentexamples the valve structure may take different forms. In one examplethe first valve structure is a siphon. This may be structured such thatopening the valve structure comprises reducing the rotational rate ofthe cartridge so that fluid is able to enter and pass through the siphonby capillary forces. In other examples the first valve structure may befor example a hydrophobic valve, a wax valve, a mechanical valve or amagnetic valve.

The method further comprises holding the portion of the blood plasma inthe processing chamber. The blood plasma mixes with the reagent andcombines with the at least one specific binding partner to form the atleast one analyte-specific binding partner complex.

The method further comprises releasing the seal to enable a first partof the washing buffer to enter the measurement structure.

The method further comprises opening the second valve structure totransfer the at least one analyte-specific binding partner complex tothe measurement structure and controlling the rotational rate ofcartridge to allow the at least one analyte-specific binding partnercomplex to flow to the measurement structure through the second valvestructure. If the second valve structure is a siphon then the process ofopening the second valve and controlling the rotational rate may beidentical. In other examples the second valve structure may be one ofthe alternative valve structures described for the first valvestructure. In this case the second valve structure may in some examplesbe opened before the rotational rate of the cartridge is controlled. Inother examples the opening of the second valve structure and thecontrolling of the rotational rate of the cartridge are performed at thesame time.

The method further comprises controlling the rotational rate of thecartridge to allow the at least one analyte-specific binding partnercomplex to flow across the membrane to the absorbent structure at adefined velocity and to allow the at least one analyte-specific bindingpartner complex to bind to the immobilized binding partner.

The method further comprises controlling the rotational rate of thecartridge to allow the first part of the washing buffer to flow acrossthe membrane to the absorbent structure at a defined velocity.

The method further comprises performing the measurement using themembrane and using the optical measurement system to measure thequantity of the analyte.

In some examples, the reagent contained in the processing chamber may bea dry chemical formulation. In other examples the reagent may be in theform of a liquid.

In some examples, the reagent can be located within the processingchamber in different ways: coated onto the surface of the processingchamber, coated onto the surface of beads which are added into theprocessing chamber, added as a lyophilisate/powder, added as capsules,added as a matrix (e.g. paper) comprising the dissolvable reagent and/orvesicles.

The chromatographic membrane may be referred to as a capillary-activezone. In one embodiment, the capillary-active zone comprises a porous,absorbent matrix. In one embodiment of the test element according to theinvention, the second end of the capillary-active zone near to the axisadjoins a further absorbent material or an absorbent structure such thatit can take up liquid from the capillary-active zone. Thecapillary-active zone and the further absorbent material typicallyslightly overlap for this purpose. The further material or the furtherabsorbent structure serve on the one hand, to assist the suction actionof the capillary-active zone and in particular of the porous, absorbentmatrix and, on the other hand, serve as a holding zone for liquid whichhas already passed through the capillary-active zone. In this connectionthe further material can consist of the same materials or differentmaterials than the matrix. For example, the matrix can be a membrane andthe further absorbent material can be a fleece or a paper. Othercombinations are of course equally possible.

The test element according to one embodiment is characterized in oneembodiment by the fact that the sample channel contains zones ofdifferent dimensions and/or for different functions. For example, thesample channel can contain a zone which contains reagents that aresoluble in the sample or can be suspended in the sample. These reagentscan be dissolved or suspended in the liquid sample when it flows into orthrough the channel and can react with the analyte in the sample or withother sample components.

The different zones in the sample channel can also differ in that thereare zones with capillary activity and those without capillary activity.Moreover, there may be zones having a high hydrophilicity and those witha low hydrophilicity. The individual zones can quasi seamlessly mergeinto one another or be separated from one another by certain barrierssuch as valves and in particular non-closing valves such as geometricvalves, siphons or hydrophobic barriers.

The test element may contain a reagent zone which contains a conjugateof an analyte binding partner (typically an antibody or animmunologically active antibody fragment capable of analyte binding ifthe analyte is an antigen or hapten, or an antigen or hapten if theanalyte is an antibody) and a label which can be detected directly orindirectly by visual, optical or electrochemical means, wherein theconjugate can be dissolved by the liquid sample. Suitable labels are,for example, enzymes, fluorescent labels, chemiluminescent labels,electrochemically active groups or so-called direct labels such as metalor carbon labels or colored latices. This zone may also be referred toas the conjugate zone.

The conjugate zone can serve also as a sample application zone or aseparate sample application zone can be located on the test element. Theconjugate zone can, in addition to the conjugate of analyte bindingpartner and label described above, also contain an additional conjugateof a second analyte binding partner (which is in turn typically anantibody or an immunologically active antibody fragment capable ofanalyte binding) and a tagging substance which is itself a partner in abinding pair. The tagging substance can for example be biotin ordigoxigenin and can be used to immobilize a sandwich complex consistingof labelled conjugate, analyte and tagged conjugate in the detectionand/or control zone.

The test element may additionally comprise a detection zone whichcontains a permanently immobilized binding partner (i.e., one thatcannot be detached by the liquid sample) for the analyte or forcomplexes containing the analyte. The immobilized binding partner is inturn typically an antibody or an immunologically active antibodyfragment capable of analyte binding or an antigen or (poly)hapten. Ifone of the above-mentioned tagged conjugates is used which for examplecomprises biotin or digoxigenin together with an analyte bindingpartner, the immobilized binding partner can also be streptavidin orpolystreptavidin and an anti-digoxigenin antibody.

Finally, there may also be a control zone in or on the test elementwhich contains a permanently immobilized binding partner for theconjugate of analyte binding partner and label for example in the formof an immobilized polyhapten which acts as an analyte analogue and isable to bind the analyte binding partner from the labelled conjugate. Itis important for the invention that the control zone may additionallycontain one or more permanently immobilized binding partner(s) for theanalyte or for complexes containing the analyte. The latter bindingpartners can be selected from the same compounds which were describedabove in connection with the immobilized binding partners of thedetection zone. These immobilized binding partners in the detection zoneand in the control zone are typically identical. They may, however, alsobe different for example in that a binding partner for a biotin-taggedconjugate (hence, e.g., polystreptavidin) is immobilized in thedetection zone and an anti-analyte antibody is immobilized in thecontrol zone in addition to the polyhapten. In the latter case theanti-analyte antibody that is additionally immobilized in the controlzone should be directed against (another) independent epitope and thusone that is not recognized by the conjugate antibodies (biotin-taggedconjugate and labelled conjugate).

The capillary-active zone is typically a porous, absorbent matrix and inparticular can be a paper, a membrane, a micro-structured polymerstructure (e.g. comprising micro-structured pillars) or a fleece.

The capillary-active zone and in particular the porous, absorbent matrixcan contain one or more zones containing immobilized reagents.

Specific binding reagents for example specific binding partners such asantigens, antibodies, (poly) haptens, streptavidin, polystreptavidin,ligands, receptors, nucleic acid strands (capture probes) are typicallyimmobilized in the capillary-active zone and in particular in theporous, absorbent matrix. They are used to specifically capture theanalyte or species derived from the analyte or related to the analytefrom the sample flowing through the capillary-active zone. These bindingpartners can be present immobilized in or on the material of thecapillary-active zone in the form of lines, points, patterns or they canbe indirectly bound to the capillary-active zone e.g., by means ofso-called beads. Thus, for example, in the case of immunoassays oneantibody against the analyte can be present immobilized on the surfaceof the capillary-active zone or in the porous, absorbent matrix whichthen captures the analyte (in this case an antigen or hapten) from thesample and also immobilizes it in the capillary-active zone such as,e.g., the absorbent matrix. In this case the analyte can be madedetectable for example by means of a label that can be detectedvisually, optically or fluorescence-optically by further reactions, forexample by additionally contacting it with a labelled bindable partner.

In another embodiment, the cartridge further comprises an aliquotingchamber. The cartridge further comprises a fluid duct connecting thefluid chamber with the aliquoting chamber. The cartridge furthercomprises a metering chamber. The cartridge further comprises aconnecting duct which fluidically connects the metering chamber with thealiquoting chamber. The measurement structure is connected to themetering chamber via a third valve structure. The fluidic elements mayhave any of the alternative forms identified for the first and secondvalve structures. The cartridge further comprises a vent connected tothe metering chamber. The vent is nearer to the rotational axis than themetering chamber.

The step of releasing the seal enables the washing buffer to enter thealiquoting chamber. The method further comprises the step of controllingthe rotational rate of the cartridge to enable the washing buffer in thealiquoting chamber to transfer into the connecting duct and to fill themetering chamber a first time. The method further comprises controllingthe rotational rate of the cartridge to transfer the first part of thewashing buffer from the metering chamber through the valve into themeasurement structure and to transfer a first remaining part back intothe aliquoting chamber.

The method further comprises the step of controlling the rotational rateof the cartridge to allow the washing buffer in the aliquoting chamberto transfer into the connecting duct and to fill the metering chamber asecond time. The method further comprises the step of controlling therotational rate of the cartridge to transfer a second part of thewashing buffer from the metering chamber through the valve into themeasurement structure and to transfer a second remaining part back intothe aliquoting chamber. The method further comprises the step ofcontrolling the rotational rate of the cartridge to allow the secondpart of the washing buffer to flow across the membrane to the absorbentstructure. The use of the structure described above may be beneficialbecause it may provide accurately metered amounts of washing buffer tobe used in subsequent washing steps. This may also be beneficial becauseit is not necessary to add fluid to the cartridge using a pipettingsystem or other means in order to have multiple steps of using thewashing buffer.

In another embodiment, the processing chamber contains a first specificbinding partner of the analyte with a detectable label and a secondspecific binding partner with a capture label. These both form a bindingcomplex in with the analyte. This may consist of a first specificbinding partner, a second specific binding partner and an analyte. Thismay additionally provide for a measurement structure within theimmobilized binding partner specific to the capture label of the secondspecific binding partner.

In another embodiment the detection is fluorescence-based. In anotherembodiment the label is particle-based fluorescent label.

In another embodiment the measurement structure contains an opticalcalibration zone. The optical calibration zone may for example be aregion on the measurement structure which contains a defined amount ofthe immobilized label and provides a means for checking if the optics ofthe instrument is functioning properly and if not, to calibrate itadequately. In other embodiments, the optical calibration zone islocated at different locations on the test element.

In another embodiment the measurement structure contains a reagent andflow control zone. This may provide for a means of checking if thecartridge is functioning properly in terms of reagents andimmunochromatography. There may be for example two different controlzones, a reagent/flow-control and an optical calibration zone asinstrument control zone for correcting the intensity of the radiation orexcitation source when an optical measurement is made. In anotherembodiment the measurement is the measurement of a concentration ofcardiac troponin.

In another embodiment each of the at least one reagent is dry. The useof dry reagents may be beneficial because they may be stored directly onthe test element in a stable manner and provide accurate results afterbeing stored large period of time.

In another embodiment each of the at least one reagent is provided in adry-chemical formulation. The use of dry reagents may be beneficialbecause they may be stored directly on the test element in a stablemanner and provide accurate results even after being stored a largeperiod of time.

In another aspect, an embodiment of the invention provides for a medicalsystem for determining a quantity of an analyte in a blood sample usinga cartridge. The medical system comprises the cartridge. The cartridgeis operable for being spun around a rotational axis. The cartridgecomprises an inlet for receiving a blood sample. The cartridge furthercomprises a blood separation chamber for separating blood plasma fromthe corpuscular blood sample by centrifugation. The blood separationchamber is fluidically connected to the inlet. The cartridge furthercomprises a processing chamber containing at least one reagent. The atleast one reagent comprises at least one specific binding partner whichis operable to bind with the analyte to form at least oneanalyte-specific binding partner complex. The cartridge furthercomprises a first valve structure connecting the blood separationchamber to the processing chamber. The cartridge further comprises ameasurement structure for enabling measurement of the quantity of theanalyte.

The measurement structure comprises a chromatographic membrane. Thechromatographic membrane comprises an immobilized binding partner fordirect or indirect binding of the analyte or the at least oneanalyte-specific binding partner complex. The measurement structurefurther comprises an absorbent structure. The absorbent structure isnearer to the rotational axis than the membrane. The cartridge furthercomprises a second valve structure connecting the processing chamber tothe measurement structure. The cartridge further comprises a fluidchamber filled with a washing buffer. The fluid chamber is fluidicallyconnected to the measurement structure. A seal keeps the washing bufferwithin the fluid chamber.

The cartridge further comprises an aliquoting chamber. The cartridgefurther comprises a fluid duct connecting the fluid chamber with thealiquoting chamber. The cartridge further comprises a metering chamber.The cartridge further comprises a connecting duct which fluidicallyconnects the metering chamber with the aliquoting chamber. Themeasurement structure is connected to the metering chamber via a thirdvalve structure. The cartridge further comprises a vent connected to themetering chamber. The vent is nearer to the rotational axis than themetering chamber.

In another aspect, the metering chamber has sidewalls and a centralregion. The sidewalls taper away from the central region. The capillaryaction next to the sidewalls of the metering chamber is greater than inthe central region of the metering chamber. This may facilitate thefilling of the metering chamber with the reduced chance of being bubbleswithin the metering chamber. This may result in a more accurate meteringof fluid dispensed from the metering chamber.

In another embodiment, the metering chamber is operable for causingfluid to fill the metering chamber using capillary action. Theconnecting duct comprises a duct entrance in the aliquoting chamber. Theconnecting duct further comprises a duct exit in the metering chamber.The duct exit is closer to the rotational axis than the duct entrance.The connecting duct is operable for causing fluid to flow to themetering chamber using capillary action. This embodiment may bebeneficial because it may provide for an accurate way of providingmultiple aliquotations per fluid which are metered accurately.

In another embodiment the connecting duct comprises a duct entrance inthe aliquoting chamber. The connecting duct further comprises a ductexit in the metering chamber. A circular arc about the rotational axispasses through both the duct entrance and the duct exit. This embodimentmay be beneficial because it may provide a very effective means ofproviding multiple volumes of buffer fluid which are accurately metered.

In another embodiment, the cartridge further comprises an overflowchamber connected to the blood separation chamber. The overflow chambercomprises an opening. The first siphon comprises a siphon entrance inthe blood separation chamber. The first siphon comprises a siphon exitin the processing chamber. The opening is closer to the rotational axisthan the siphon exit. The siphon entrance can be closer to therotational axis than the siphon exit. This embodiment may have thebenefit that all of the fluid from the blood separation chamber istransferred to the processing chamber.

In another embodiment, the cartridge further comprises an overflowchamber connected to the blood separation chamber. The overflow chambercomprises an opening. The first siphon comprises a siphon entrance inthe blood separation chamber. The first siphon comprises a siphon exitin the processing chamber. The opening is closer to the rotational axisthan the siphon exit. The siphon exit can be closer to the rotationalaxis than the siphon entrance. This embodiment may have the benefit thatnot all of the fluid from the blood separation chamber is transferred tothe processing chamber. This may reduce the amount of fatty materials inthe blood plasma which are transferred to the processing chamber. Thismay result in a higher quality analysis than would be performed if thesiphons were in a different location.

In another embodiment the first siphon comprises a nearest location thatis closes to the rotational axis. The distance of the first siphon tothe rotational axis changes monotonically between the siphon entranceand the nearest location. The distance of the first siphon to therotational axis changes monotonically between the siphon exit and thenearest location.

In another embodiment the processing chamber comprises at least twosub-processing chambers. Each of the at least two sub-processingchambers are fluidically connected by an intermediate valve structure.The intermediate valve structure may be any of the alternate valvestructure types discussed for the first or second valve structure. Theprocessing chamber contains two or more reagents. Each of the at leasttwo sub-processing chambers contains a portion of the two or morereagents. The two or more reagents may be divided into distinct reagentregions within each of the two sub-processing chambers or there may be amixture of the two or more reagents within both of the sub-processingchambers. This embodiment may be advantageous because it enables theblood plasma to be processed by different reagents in a sequentialorder. This may enable more complicated tests to be performed with thecartridge. The use of two or more sub-processing chambers for storingdifferent reagents can also be advantageous if reagents have to bestored on the cartridge which would react with each other because by thespatial split of the different reagents into different sub-processingchambers an unintentional reaction between the reagents could beprevented.

In another embodiment, the medical system further comprises a cartridgespinner for controlling the rotation of the cartridge about therotational axis.

In another embodiment, the medical system comprises a memory for storingmachine-executable instructions and a processor for controlling themedical system. Execution of the machine-executable instructions causesthe processor to rotate the cartridge about the rotational axis totransport the blood sample into the blood separation chamber bycontrolling the cartridge spinner. Execution of the machine-executableinstructions further causes the processor to control the rotation of thecartridge about the rotational axis to separate the blood plasma fromthe corpuscular blood sample components by centrifugation by controllingthe cartridge spinner. Execution of the machine-executable instructionsfurther causes the processor to open the first valve structure androtate the cartridge about the rotational axis to transport a definedportion of the blood plasma from the blood separation chamber to theprocessing chamber by controlling the cartridge spinner. In the casewhere the first valve structure is a siphon then both the opening andthe rotation of the cartridge can be performed by controlling thecartridge spinner. If the first valve structure is another sort of valvesuch as a wax or mechanical valve or mechanical valve then a valveopening mechanism may be controlled by the processor to achieve this.This is also true of any of the other valve structures which arementioned herein.

Execution of the machine-executable instructions further causes theprocessor to hold the portion of the blood plasma in the processingchamber. This may be achieved by controlling the cartridge spinner. Theblood plasma mixes with the reagent and combines with the at least onespecific binding partner to form the at least one analyte-specificbinding partner complex. Execution of the machine-executableinstructions further causes the processor to release the seal to enablea first part of the washing buffer to enter the measurement structure.This for example may be performed by the processor controlling a sealopener which is an apparatus or mechanism which actuates the cartridgesuch as to open the seal.

Execution of the machine-executable instructions further causes theprocessor to open the second valve structure to transfer the at leastone analyte specific binding partner complex to the measurementstructure and controlling the rotational weight of the cartridge toallow the at least one analyte-specific binding partner complex to flowto the measurement structure through the second valve structure. Thismay be achieved for example by controlling the rotational rate of thecartridge with the cartridge spinner. Execution of themachine-executable instructions further causes the processor to controlthe rotational rate of the cartridge by controlling the cartridgespinner to allow the at least one analyte-specific binding partnercomplex to flow across the membrane to the absorbent structure at adefined velocity and to allow the at least one analyte-specific bindingpartner complex to bind to the mobilized binding partner. This step mayalso be achieved by controlling the rotational rate of the cartridgewith the cartridge spinner by the processor.

Execution of the machine-executable instructions further allows theprocessor to control the rotational rate of the cartridge to allow thefirst part of the washing buffer to flow across the membrane to theabsorbent structure at a defined velocity. The rotational rate of thecartridge may be controlled using the cartridge spinner. Execution ofthe machine-executable instructions further causes the processor toperform the measurement using the membrane and using the opticalmeasurement system for the analyte quantization.

In another embodiment, the medical system further comprises a sealopener. For example, the processor may be able to control the sealopener automatically. Execution of the machine-executable instructionscauses the processor to control the seal opener to release the seal toenable the washing buffer to enter the aliquoting chamber beforedecreasing the rotational rate of the cartridge to admit the washingbuffer in the aliquoting chamber to transfer into the connecting ductand to fill the metering chamber a first time.

In another embodiment the first valve structure is a first siphon. Inanother embodiment the second valve structure is a second siphon. Inanother embodiment the third valve structure is a third siphon.

In another embodiment, the medical system further comprises an opticalmeasurement system for performing the measurement using the membrane. Inanother embodiment, the optical measurement system is afluorescence-based detector. The fluorescence-based detector for examplemay be a spectrometer or a monochromator in some examples. In anotherembodiment, the medical system further comprises a temperaturecontroller for maintaining the temperature of the cartridge within apredetermined temperature range. This may be beneficial because themeasurement and the reagents may function better or at a controlled rateif the temperature is accurately controlled.

In another embodiment, the fluid chamber is contained within thecartridge. In another embodiment, the seal of the fluid chamber is afoil which may be pierced by a lancing structure. In another embodiment,the fluid chamber is within a blister pack or blister packaging. Theblister may be depressed and the increase in pressure may cause the sealto break releasing the fluid in the fluid reservoir. In anotherembodiment, the absorbent structure is a waste fleece. In anotherembodiment, the fluid chamber is a blister packet wherein the blisterpacket comprises a flexible wall. Depressing the flexible wall may causethe seal to open.

In another embodiment, the cartridge is molded or formed from plastic.There may be a cover which is attached to the molded portion.

In another embodiment, the blood separation chamber is also used todetermine the hematocrit of the blood sample after the completion of theseparation of blood plasma from the corpuscular blood sample components.In one example this can be done by optical determination of the volumefilled by the corpuscular blood sample components in the rotationalaxis-distant parts of the blood separation chamber of the aftercentrifugation of the test element and of the volume filled by bloodplasma in the rotational axis-near parts of the blood separation chamberof the after centrifugation of the test element. These two volumes canbe correlated to each other to obtain a parameter which relates to thehematocrit of the blood sample.

In another example, the analyte quantitation is performed without anywashing steps. Method steps detailing controlling the rotational rate ofthe cartridge to control the flow of washing buffer across thechromatographic membrane to the absorbent structure at a definedvelocity may therefore be deleted from the claims.

In another embodiment, a preliminary value for the analyte quantitationis generated by performing an optical measurement after thechromatography of the processed sample before washing the membrane withthe washing buffer. This may give an indication for a high analyteconcentration within the sample and allows sending an early alarm to theuser in case of high analyte quantity or concentration. In anotherexample, the analyte quantitation is performed by using serum, plasma orurine as sample. Regarding the different immunoassay formats we can alsorefer to US 2009/0191643 for more details.

It is understood that one or more of the aforementioned embodimentsand/or examples of the invention may be combined as long as the combinedembodiments are not mutually exclusive.

It is also understood that method steps and/or actions performed by theprocessor in response to the machine executable instructions may beperformed in different orders as long as the re-arrangement does notlead to a self contradictory order of actions or method steps. Inparticular, the steps (and equivalent actions performed by theprocessor) of opening the second valve structure to transfer the atleast one analyte specific binding partner complex to the measurementstructure and controlling the rotational rate of the cartridge to allowthe at least one analyte specific binding partner complex to flow to themeasurement structure through the second valve structure and ofcontrolling the rotational rate of the cartridge to allow the at leastone analyte specific binding partner complex to flow across the membraneto the absorbent structure at a defined velocity and to allow the atleast one analyte specific binding partner complex to bind to theimmobilized binding partner; may be performed before releasing the sealto enable a first part of the washing buffer to enter the measurementstructure.

It is also understood that method steps and/or actions performed by theprocessor in response to the machine executable instructions are notlimited to the particular order as described above and as is defined inthe claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the following embodiments of the invention are explained in greaterdetail, by way of example only, making reference to the drawings inwhich:

FIG. 1 illustrates an example of a cartridge;

FIG. 2 shows a further view of the cartridge of FIG. 1;

FIG. 3 shows a further view of the cartridge of FIG. 1;

FIG. 4 shows an alternative to the components illustrated in FIG. 3;

FIG. 5 shows an alternative to the processing chamber of the illustratedin FIG. 1;

FIG. 6 shows a symbolic diagram which illustrates the principle of howthe quantitative analyte can be determined using the cartridge;

FIG. 7 illustrates an example of an automatic analyzer;

FIG. 8 shows a flow chart which illustrates a method of operating theautomatic analyzer of FIG. 7;

FIGS. 9a, 9b and 9c illustrate graphically a method determining aquantity of analyte in a blood sample using the cartridge of FIG. 1;

FIG. 10 illustrates a metering structure for performing multiplealiquots of a fluid;

FIG. 11 illustrates a cross sectional view of a metering chamber;

FIG. 12 illustrates part of a method of performing a dispensing fluidusing the metering structure of FIG. 10;

FIG. 13 further illustrates part of a method of performing a dispensingfluid using the metering structure of FIG. 10;

FIG. 14 further illustrates part of a method of performing a dispensingfluid using the metering structure of FIG. 10;

FIG. 15 further illustrates part of a method of performing a dispensingfluid using the metering structure of FIG. 10;

FIG. 16 further illustrates part of a method of performing a dispensingfluid using the metering structure of FIG. 10;

FIG. 17 further illustrates part of a method of performing a dispensingfluid using the metering structure of FIG. 10;

FIG. 18 further illustrates part of a method of performing a dispensingfluid using the metering structure of FIG. 10;

FIG. 19 illustrates an alternative metering structure for performingmultiple aliquots of a fluid;

FIG. 20 illustrates part of a method of performing a dispensing fluidusing the metering structure of FIG. 19;

FIG. 21 further illustrates part of a method of performing a dispensingfluid using the metering structure of FIG. 19;

FIG. 22 further illustrates part of a method of performing a dispensingfluid using the metering structure of FIG. 19;

FIG. 23 further illustrates part of a method of performing a dispensingfluid using the metering structure of FIG. 19;

FIG. 24 further illustrates part of a method of performing a dispensingfluid using the metering structure of FIG. 19;

FIG. 25 further illustrates part of a method of performing a dispensingfluid using the metering structure of FIG. 19; and

FIG. 26 further illustrates part of a method of performing a dispensingfluid using the metering structure of FIG. 19.

DETAILED DESCRIPTION

Like numbered elements in these figures are either equivalent elementsor perform the same function. Elements which have been discussedpreviously will not necessarily be discussed in later figures if thefunction is equivalent.

FIGS. 1 and 2 show an example of a cartridge 100. FIG. 1 shows a frontview of the cartridge 100. FIG. 2 shows a backside view of the cartridge100. The cartridge is adapted for rotating around a rotational axis 102.The cartridge 100 is predominantly flat and has an outer edgeperpendicular to the rotational axis 102. The outer edge 104 is lessthan a particular radius and is predominantly circular in shape. In theembodiment shown in FIGS. 1 and 2 there are also several optional flatportions 106 of the outer edge. These may aid in gripping or storing thecartridge 100. In alternative embodiments such flat portions are lackingand the overall outer edge of the cartridge is predominantly circular inshape. The cartridge 100 could for example be made out of moldedplastic. There may be a cover which is placed on the surface of thestructure shown in FIG. 1. The cover is not shown so as to aid the viewof the microfluidic structure within the cartridge 100.

The cartridge 100 is shown as having a blood inlet 108 where a bloodsample can be added or pipetted into the cartridge 100. The blood inlet108 may for example comprise a storage chamber 110 for storing a volumeof a blood sample. The storage chamber 110 is shown as having anexpansion chamber 112 with a vent 114. The various microfluidicstructures may be shown as having expansion chambers 112 and vents 114also. There may also be failsafe indicators 116 which are regions of themicrofluidic structure which fill with fluid to indicate that amicrofluidic structure has received a sufficient amount of fluid orsample. These for example may be checked optically during the use of thecartridge 100. These in some cases are labeled but are not discussedherein. The blood inlet 108 is shown as being fluidically connected to ablood separation chamber 118. The blood separation chamber 118 is usedto separate the plasma from the corpuscular blood sample components(blood cells) in a blood sample. The blood separation chamber 118 isshown as also being connected to an overflow chamber 120 that accepts anexcess of plasma from the blood sample. The functioning of the bloodseparation chamber 118 will be described in more detail below. The bloodseparation chamber 118 is connected to a processing chamber 124 via afirst valve structure 122.

In this example the first valve structure 122 is a siphon. It couldhowever include other structures such as a mechanical, magnetic, orthermally activated valve. The processing chamber 124 is shown ascontaining several surfaces 126 which could be used for storing a dryreagent. In other examples there may be amounts of liquid or other typesof reagent which can be mixed with a plasma sample. The processingchamber 124 is shown as being connected to a measurement structure 130via a second valve structure 128. In this example the second valvestructure 128 is a siphon. The second valve structure 128 could take anyof the forms that the first valve structure 122 can also take. In thisexample the processing chamber 124 is shown as being a single chamber.In another example the processing chamber 124 may comprise severalsub-chambers so that a plasma sample can be processed by differentreagents sequentially. The measurement structure 130 is shown ascontaining a chromatographic membrane 134 and in contact with therotational axis-nearer end of the chromatographic membrane an additionalabsorbent structure 132 which serves as a waste fleece. The reagents andthe chromatographic membrane 134 are discussed in greater detail below.

After being processed with a reagent the plasma sample may be wicked ortransported across the chromatographic membrane 134. Before and/or aftera washing buffer may be used to prime or wash the chromatographicmembrane 134. The cartridge 100 shown in FIGS. 1 and 2 is a cartridgewhich incorporates a number of distinct optional features. On thebackside of the cartridge 100 is shown a fluid chamber 136. In thisexample the fluid chamber 136 is a blister pack or flexible fluidchamber which can be compressed from outside of the cartridge 100. Whenthe fluid chamber 136 is compressed a seal is broken which allows fluidwithin the fluid chamber 136 to enter a fluid duct 138. The fluid duct138 then transports fluid to a metering structure 140.

The metering structure 140 enables the washing buffer to be supplied tothe measurement structure 130 multiple times in precisely measuredamounts. The metering structure 140 is however not necessary. There maybe examples where the washing buffer is delivered directly to themeasurement structure 130. In other examples the measurement structureis not primed with the washing buffer before the test is performed. Thestructure labeled 136′ is an alternate fluid chamber. The fluid chamber136′ may be mechanically actuated to break a seal around its perimeterwhich causes fluid to enter the metering structure 140 via the fluidduct 138′. The cartridge 100 is also shown as containing anotheroptional structure. The structure labeled 142 is a manual fill locationwhere a reagent or buffer solution may be added manually to themeasurement structure 130 or by an external source like a dispenser.

The metering structure 140 is shown as containing an aliquoting chamber144. The aliquoting chamber 144 receives the fluid from the fluidchamber 136 or 136′. The aliquoting chamber 144 is connected to ametering chamber 146 via a connecting duct 148. The metering structure146 is used to accurately meter the buffer fluid and supply meteredaliquots of the fluid one or more times to the measurement structure130. The metering structure 146 is connected to the measurementstructure 130 via a fluidic element 150. In this case the fluidicelement 150 is shown as containing a microfluidic duct or channel and achamber for holding a quantity of the buffer fluid as it is beingmetered. The function of the metering structure 140 and severalalternatives will be discussed with reference to later Figs.

FIG. 3 shows an enlarged region of FIG. 1 which illustrates the bloodseparation chamber 118 and the processing chamber 124 in greater detail.The separation chamber 118 is shown as containing an upper portion 300and a lower portion 302. The upper portion 300 is closer to therotational axis 102. The overflow chamber is shown as having an overflowopening 304. The overflow opening 304 sets the maximum volume of fluidwithin the blood separation chamber 118. In this example the first valvestructure 122 is a siphon. It may also be referred to as a first siphon.The first siphon 122 has a siphon entrance 306 in the blood separationchamber 118. The first siphon 122 also has a siphon exit 308 into theexpansion chamber 112′. In this example there is an additional expansionchamber 112′ located between the blood separation chamber 118 and theprocessing chamber 124. In other examples the siphon exit 308 may bedirectly connected to the processing chamber 124.

The expansion chamber 112 enables the processing chamber 124 to belocated further from the rotational axis. This may in some instancesprovide additional space for the processing chamber 124. In examiningFIG. 3 it can be seen that the siphon exit 308 is closer to therotational axis 102 than the siphon entrance 306. This is done becauseit traps an additional amount of blood plasma within the upper portion300. The last bit or amount of blood plasma may contain fatty or oilytissues which are contained in the blood plasma. Placing the siphon exit308 closer to the rotational axis 102 may reduce the amount of thismaterial in the blood plasma which is ultimately transferred to theprocessing chamber 124. This may result in a superior or more accuratemeasurement of the analyte.

It can be seen that the first siphon 122 has a nearest location 310 tothe rotational axis 102. Between the nearest location 310 and the siphonexit 308 the distance to the rotational axis 102 increasesmonotonically.

FIG. 4 shows a further enlarged region of the cartridge 100. The regionof FIG. 4 is identical to that of FIG. 3. In the example shown in FIG. 4the first valve structure 122 and the second valve structure 128 havebeen modified. The first valve structure 122 comprises a valve element400 and the second valve structure 128 comprises a valve element 402.The valve element 400 and 402 may be mechanical valves which may beopened and/or closed through a variety of means. For example the valveelements 400, 402 could be mechanically actuated, they could comprise awax or other material which is melted by heat, as well as they could bemagnetically operated, or actuated using other means.

FIG. 5 shows a modification of the cartridge 100 shown in FIG. 1. In theexample shown in FIG. 5 the processing chamber 124 has been broken intotwo separate sub-chambers 500 and 502.

The first valve structure 122 is connected to the first sub-chamber 500.There is then an intermediate valve structure 504 between the firstsub-chamber 500 and the second sub-chamber 502. The second valvestructure 128 is then connected from the second sub-chamber 502 to themeasurement structure 130. The two sub-chambers 500, 502 can be used toprocess the blood plasma sequentially with different reagents.

FIG. 6 shows a symbolic diagram which illustrates the principle of howthe quantitative analyte is determined using the cartridge. 600represents a blood sample and 602 the analyte present in the blood 600.The arrow 604 represents the generation of plasma by centrifugation.602′ represents the analyte 602 in plasma. The arrow 606 represents themixing of plasma with a dried assay reagent and incubation in theprocessing chamber. Reference symbol 124 represents the processingchamber. In the processing chamber a capture antibody 608 and adetection antibody 610 attach to the analyte 602′ in the plasma. Thecombination of the capture antibody 608 and the detection antibody 610with the analyte 602′ forms an analyte specific binding partner complex611. Arrow 609 represents the transport to the measurement structure.

The arrows 612 represent the plasma transport through thechromatographic membrane 134 of the measurement structure. The threebars 614, 616 and 618 represent three different zones on thechromatographic membrane 134. Reference symbol 614 represents a captureand detection zone. Bar 616 represents an instrument control zone. Bar618 represents an assay control zone. In the capture and detection zone614 there may be a capture element 620 that bonds to the captureantibody 608. For example the capture element could be streptavidin andthe capture antibody could be biotinylated. When the capture antibody608 comes in contact with the capture element 620 it bonds fast to thecapture antibody 608 and thereby to the complete analyte specificbinding partner complex 611. The detection antibody 610 which is part ofthis bound analyte specific binding partner complex 611 is thereby alsoimmobilized at this location and can then be detected later. For examplethe detection antibody 610 contains a fluorescent label such asfluorescent-latex. The instrument control zone 616 may contain also alatex with the fluorescent marker. This can be used to check if theoptical measurement system of the instrument is functioning properlyand/or to calibrate this optical measurement system. In the assaycontrol zone 618, excess detection antibody 610 bonds to an artificialanalyte line 622. The regions 616 and 618 are used as a control toensure that the cartridge 100 and the optical measurement system of theinstrument are functioning properly.

The scheme explained in FIG. 6 when used with the cartridge of FIG. 1may in some instance provide better measurement results than when usingstandard laboratory methods. For example the concentration of cardiactroponin was tested using equivalent microfluidic structures in a disc.The results of these tests indicate that the accuracy andreproducibility of the measurements is superior to that obtained in atypical analytical laboratory.

In an embodiment, antibodies which can be used for the detection ofhuman cardiac troponin T are antibodies recognizing the linear epitopeELVSLKD of human cardiac Troponin (P45379, UniProt database) which islocated at the amino acid positions 129-135 of P45379 (UniProt database)or recognizing the linear epitope QQRIRNEREKE of human cardiac Troponin(P45379, UniProt database) which is located at the amino acid positions147-157 of P45379 (UniProt database) or recognizing the linear epitopeQQRIRNERE of human cardiac Troponin (P45379, UniProt database) which islocated at the amino acid positions 147-155 of P45379 (UniProtdatabase). In an embodiment, these antibodies are monoclonal mouseantibodies. In an embodiment, a combination of a first antibodyrecognizing the linear epitope ELVSLKD of human cardiac Troponin(P45379, UniProt database) which is located at the amino acid positions129-135 of P45379 (UniProt database) and a second antibody recognizingeither the linear epitope QQRIRNEREKE of human cardiac Troponin (P45379,UniProt database) which is located at the amino acid positions 147-157of P45379 (UniProt database) or the linear epitope QQRIRNERE of humancardiac Troponin (P45379, UniProt database) which is located at theamino acid positions 147-155 of P45379 (UniProt database) is used todetect human cardiac Troponin T in a sandwich assay format. In anotherembodiment a combination of a labelled detection antibody recognizingthe linear epitope ELVSLKD of human cardiac Troponin (P45379, UniProtdatabase) which is located at the amino acid positions 129-135 of P45379(UniProt database) and a capture antibody recognizing either the linearepitope QQRIRNEREKE of human cardiac Troponin (P45379, UniProt database)which is located at the amino acid positions 147-157 of P45379 (UniProtdatabase) or the linear epitope QQRIRNERE of human cardiac Troponin(P45379, UniProt database) which is located at the amino acid positions147-155 of P45379 (UniProt database) is used to detect human cardiacTroponin T in an sandwich assay format. In another embodiment, the labelof the labelled detection antibody is a fluorescent latex particle.

FIG. 7 shows an example of a medical system 700. The medical system 700is adapted for receiving a cartridge 100. There is a cartridge spinner702 which is operable for rotating the cartridge 100 about therotational axis. The cartridge spinner 702 has a motor 704 attached to agripper 706 which attaches to a portion of the cartridge 708. Thecartridge 100 is shown further as having a measurement or transparentstructure 710. The cartridge 100 can be rotated such that themeasurement structure 710 goes in front of an optical measurement system712 which can perform for example an optical measurement of the quantityof the analyte. An actuator 711 is also shown in this figure. It can beused to open fluid reservoirs in the cartridge 100. There may also beadditional actuators or mechanisms for actuating mechanical valves orvalve elements on the cartridge if they are present.

The actuator 711, the cartridge spinner 702, and the measurement system712 are shown as all being connected to a hardware interface 716 of acontroller 714. The controller 714 contains a processor 718 incommunication with the hardware interface 716, electronic storage 720,electronic memory 722, and a network interface 724. The electronicmemory 730 has machine executable instructions which enable theprocessor 718 to control the operation and function of the medicalsystem 700. The electronic storage 720 is shown as containing ameasurement 732 that was acquired when instructions 730 were executed bythe processor 718. The network interface 724 enables the processor 718to send the measurement 732 via network connection 726 to a laboratoryinformation system 728.

FIG. 8 shows a flowchart, which illustrates a method of operating themedical system 700 of FIG. 7. The steps in FIG. 8 for example may bemachine-executable instructions that are included in the instructions730. Before the method of FIG. 8 is performed a blood sample for examplemay be placed into the inlet and then the cartridge 100 is placed intothe medical system 700. First in step 800 the processor 718 controls themotor 704 such that the cartridge is rotated about the rotational axisto transport the blood sample into the blood separation chamber. Next instep 802 the processor 718 further controls the motor 704 such that therotation of the cartridge about the rotational axis separates the bloodplasma from the corpuscular blood sample components by centrifugation.Next in step 804 the processor 718 controls the motor 704 such that thefirst valve structure is opened and the cartridge is rotated about therotational axis at a sufficient velocity to transport a defined portionof the blood plasma from the blood separation chamber to the processingchamber. In the case where the valve structures comprise mechanicalvalve elements there may be an additional mechanism or apparatus thatthe processor controls 718 to open these mechanical valve elements.

Next in step 806 the processor 718 controls the rotation rate of themotor 704 such that the portion of the blood plasma is held in theprocessing chamber. During this time the blood plasma mixes with thereagent and combines with at least one specific binding partner to formthe at least one analyte-specific binding partner complex. Next in step808 a seal is released to enable a first part of the washing buffer toenter the measurement structure by the processor 718. For example theprocessor 718 may control the actuator 711 to compress the fluid chamber136 shown in FIG. 2. Next in step 810 the processor 718 controls therotation rate of the motor 704 such that the second valve structure isopened to transfer the at least one specific binding partner complex tothe measurement structure and such that the cartridge allows the atleast one analyte-specific binding partner complex to flow to themeasurement structure through the second valve structure. Again if thesecond valve structure comprises a mechanical valve element then theprocessor may also control an additional apparatus or mechanism to openthis mechanical valve element.

Next in step 812, the processor 718 controls the rotational rate of themotor 704 such that the cartridge allows the at least oneanalyte-specific binding partner complex to flow across the membrane tothe absorbent structure at a defined velocity and to allow the at leastone analyte-specific binding partner complex to bind to the immobilizedbinding partner. In step 814 the processor 718 controls the rotationalrate of the motor 704 such that the cartridge spins at a rate thatallows the first part of the washing buffer to flow across the membraneto the absorbent structure at a defined velocity. In alternateembodiments the step 808 (releasing the seal to enable a first part ofthe washing buffer to enter the measurement structure) is performeddirectly before step 814. Finally in step 816 the processor 718 controlsthe optical measurement system 712 to perform the measurement using theoptical measurement system. This measurement 732 may then be transformedinto an analyte quantity or concentration.

FIGS. 9A, 9B and 9C illustrate graphically a method determining aquantity of analyte in a blood sample using the cartridge 100. Themethod is illustrated graphically in FIGS. 9A, 9B and 9C. Image 900shows the cartridge 100 in its initial condition. Next in step 902 bloodis placed into the inlet. Next in step 904 the blood sample istransferred to the blood separation chamber. In step 906 the plasma isseparated from the red blood cells by centrifugation. Next in step 908the blood plasma is transferred to the processing chamber. Next in step910 the blood plasma is mixed with the reagent. In step 912 the washingbuffer is released by breaking the seal. In step 914 the incubate or thecombination of the blood plasma and the reagent is transferred to themeasurement structure.

Next in step 916 the chromatography of the analyte-specific bindingpartner complex or incubate is performed. Next in step 918 the washingbuffer is metered. In several instances the structure depicted may beused to provide multiple meterings of the washing buffer. However, thisis not necessary in all cases and it is possible that only the fluidfrom the fluid chamber is transferred and that there is no meteringstep. Next in step 920 the washing buffer is transferred to themeasurement structure and wicked across the chromatographic membrane 134into the absorbent structure 132, as shown in step 922. Finally, in step924 the measurement of the analyte is performed using a fluorescencemeasurement.

FIG. 10 shows an example of a metering structure 140. The meteringstructure part of the fluidic components that make up a cartridge 100 asis shown in FIG. 1. There is a rotational axis labeled 102. Also shownin the Fig. is a portion of a fluid chamber 136. The fluid chamber isdesigned for having a reservoir that provides fluid via a fluid chamberduct 138 that leads into the aliquoting chamber 144. In this example thealiquoting chamber 144 is whale-shaped. There is a connecting duct 148which connects the aliquoting chamber 144 with a metering chamber 146.The connecting duct 148 has a duct entrance 1014 and a duct exit 1016.The duct entrance 1014 leads to the aliquoting chamber 144 and the ductexit 1016 leads to the metering chamber 146. A circular arc 1018 that isdrawn about the rotational axis 102 passes both through the ductentrance 1014 and the duct exit 1016. The metering chamber 146 isconnected via a tube-like structure 1020 to a fluidic element 150. Inthis example there is a valve 1021 between the tube-like structure 1020and the metering chamber 146. In this example the valve 1021 is acapillary valve.

The valve 1021 could be implemented in different ways. In somealternatives the shape of the interface between the tube-like structure1020 and the fluidic element 150 could function as a capillary valve.Alternatively a valve could be placed between the elements 1020 and 150.In other embodiments a duct could be connected in the same location anda controllable microvalve could be used instead. The controllablemicrovalve could be placed between the metering chamber 146 and thetube-like structure 1020 or between the tube-like structure 1020 and thefluidic element 150.

An optional expansion chamber 1024 is shown as bordering on an upperedge 1026 of the metering chamber 146. There is a vent 1028 which ventsthe expansion chamber 1024. The whole boundary between the meteringchamber 146 and the expansion chamber 1024 is open. This may help reducethe chances of bubbles forming in the metering chamber 146. In someexamples the expansion chamber 1024 may have a width which is greaterthan that of the metering chamber 146. Capillary forces may be used thento keep the fluid in the metering chamber 146. The dashed line labeled1030 and also A-A shows the location of a cross-sectional view of themetering chamber 146. This cross-sectional view is shown in FIG. 11. Thealiquoting chamber 144 can be shown as also having a vent 1028. Theregion around the duct entrance 1014 is in this embodimentfunnel-shaped. It may also be noted that the aliquoting chamber 144 isshown as not having sharp edges. The lack of sharp edges helps tofacilitate the movement of fluid from the aliquoting chamber 144 to theduct entrance 1014 when the disc is decelerated.

The aliquoting chamber 144 is also shown as having a connection to afluidic connection 1034 which leads to an excess fluid chamber 1032. Thefluidic connection 1034 has a fluidic connection entrance 1036. Thefluidic connection entrance 1036 defines the maximum fluid level in thealiquoting chamber 144. The maximum fluid level in the aliquotingchamber 144 is lower than the circular arc 1018. The fluidic connection1034 is connected to the excess fluid chamber 1032 via a capillary valve1038 in this embodiment. The use of a valve or a capillary valve isoptional. The excess fluid chamber is shown as having a vent 1028 and itis also connected to a fail-safe chamber 1040. When the fluid flows intothe excess fluid chamber 1032 the fail safe chamber 1040 is filled. Thefail safe chamber 1040 may be used to indicate optically if fluid hasentered the excess fluid chamber 1032. For example during use if thefail safe chamber 1040 is not filled it may indicate that the aliquotingchamber 144 was not properly filled with fluid.

FIG. 11 shows a cross-sectional view 100 of the profile A-A which islabeled 1030 in FIG. 10. In this Fig. the body of the cartridge 1102 canbe seen. There is an opening in the body 1102 for the metering chamber146. The body of the cartridge 1102 in this example is fabricated byinjection molding. The body of the cartridge is assembled from a lid1108 and a support structure 1110.

At the far end of the metering chamber the entrance into the valve 1021can be seen. The metering chamber 146 can be seen as being divided intoseveral different regions. On the edges there are two sidewalls regions1104. Between the two sidewalls regions or two side regions is a centralregion 1106. The sidewall 1104 regions become more narrow or taper awayfrom the central region 1106. This causes a narrowing in the dimensionsof the metering chamber 146 in this region. The capillary action maytherefore be higher in the sidewall regions 1104 than in the centralregion 1106. This may cause the metering chamber 146 to fill with fluidfirst in the sidewall regions 1104 before the central region 1106. Thismay have the benefit of reducing the number of bubbles which are formedor trapped in the metering chamber 146 when the metering chamber 146 isfilled with fluid.

FIGS. 12-18 illustrate how the metering structure 140 may be used toperform multiple aliquotations of fluid to the fluidic elements 150.

In FIG. 12 the disc is rotated about the rotational axis 102. The arrow1200 indicates the direction of rotation. In this particular example thedisc is spinning at 20 Hz. Fluid or washing buffer 1202 is transportedinto the aliquoting chamber 144 from the fluid chamber 136. Fluid 1202can be seen dripping from the fluid duct 138 into the aliquoting chamber144. The fluid volume in the aliquoting chamber 144 is limited andthereby metered by the fluidic connection 1034 which connects to theexcess fluid chamber 1032. The fail safe chamber 1040 can be seen asbeing filled with fluid.

Next in FIG. 13 the fluid volume 1202 has been completely transferredfrom the fluid chamber 136 into the aliquoting chamber 144. The failsafe chamber 1040 is shown as being filled with the fluid. In thisexample the disc is still spinning at the same rate as was shown in FIG.12. The aliquoting chamber 144 is filled with fluid 1202 up to themaximum fluid level 1300. It can be seen that the maximum fluid level1300 is below or further away from the rotational axis 102 than theconnecting duct 148. When the disc is spinning in this way the fluid1202 cannot enter the metering chamber 146.

Next in FIG. 14 the disc stops or is decelerated to a lower rotationalfrequency with a high rate of deceleration for example at 50 Hz persecond. The inertia of the fluid forces the fluid 1202 towards andthrough the connecting duct 148 and into the metering chamber 146. Itcan be seen in this Fig. that the fluid 1202 is filling the sides of themetering chamber 146 before it is filling the central region. This isbecause of the tapered side walls 1104 shown in FIG. 11. Capillaryaction causes this side wall portion of the metering chamber 146 to fillfirst. This manner of filling the metering chamber may reduce thechances that air bubbles form or adhere in the metering chamber 146.

In FIG. 15 the cartridge is still stationary or at a reduced rotationrate and the metering chamber 146 is completely filled with fluid 1202.The cartridge or disc may still be considered to be at rest. Thecomplete filling of the metering chamber is caused by capillary forcescaused by the respective geometrical dimensions of the metering chamber.

FIG. 16 shows the same view as is shown in FIG. 15 except a dashed line1600 has been drawn in the metering chamber 146. This line 1600 in themetering chamber 146 divides the fluid in the metering chamber intoseveral parts or portions. The fluid part 1604 radially inwards (closerto rotational axis 102) from the line 1600 may flow back into thereservoir. The radially outward part (further away from the rotationalaxis 102) or part 1602 may be completely transferred into the fluidicelements 150. The radially inward part 1604 can be referred to as theremaining part of the fluid and the radially outward part 1602 can bereferred to as the part of the fluid 1602 that is transferred into thedownstream fluidic element. The volume of the fluid 1602 is the aliquottransferred in a subsequent step to the fluidic elements 150.

Next in FIG. 17 the disc begins to accelerate and spin around in thedirection 1200. The disc accelerates; this causes the capillary valve1021 to open. The remaining part of the fluid 1604 was transferred backto the aliquoting chamber 144. The part of the fluid 1602 is in theprocess of being transferred to the fluidic elements 150. A drop of thefluid can be seen dropping from the tube 1020.

Next in FIG. 18 it can be seen that the fluid volume 1602 has beencompletely transferred to the fluidic elements 150 and is no longervisible in the Fig. The remaining part of the fluid 1604 has beentransferred back into the aliquoting chamber 144 and is mixed with theremaining fluid 1202. The first aliquotation step is finished; theprocess may be repeated again from FIG. 14 and may be repeated until thefluid volume 1202 in the aliquoting chamber 144 is smaller than thevolume of the metering chamber 146.

FIG. 19 shows an example of an alternate metering structure 140′. Themetering structure 140′ may replace the metering structure 140 inFIG. 1. The mechanical structure of the metering structure 140′ issimilar to the metering structure 140 of FIG. 10 with several mechanicaldifferences. Again, there is a rotational axis labeled 102. Also shownin the Fig. is a portion of a fluid chamber 136. The fluid chamber 136has a reservoir that provides fluid via a fluid chamber duct 138 thatleads into the aliquoting chamber 144. In this example the aliquotingchamber 144 is teapot-shaped. There is a connecting duct 148 whichconnects the aliquoting chamber 144 with a metering chamber 146. Theconnecting duct 148 has a duct entrance 1014 and a duct exit 1016. Theduct entrance 1014 leads to the aliquoting chamber 144 and the duct exit1016 leads to the metering chamber 146. The duct entrance 1014 isfurther away from the rotational axis 102 than the duct exit 1016 of theconnecting duct 148 is.

The metering chamber 146 is connected via a tube-like structure 1020 tofluidic element 150. In this example there is a valve 1021 between thetube-like structure 1020 and the fluidic elements. The valve 1021 inthis example is a capillary valve. The valve 1021 could be implementedin different ways. In some embodiments the tube-like structure 1020could functions as the capillary valve. In some embodiments a duct couldbe connected in the same location and a controllable microvalve could beused instead. The controllable microvalve could be placed between themetering chamber 146 and the tube-like structure 1020 or between thetube-like structure 1020 and the fluidic elements 150.

An expansion chamber 1024 is shown as bordering on an upper edge 1026 ofthe metering chamber 146. There is a vent 1028 which vents the expansionchamber 1024. The whole boundary between the metering chamber 146 andthe expansion chamber 1024 is open. This may help reduce the chances ofbubbles forming in the metering chamber 146. In some examples theexpansion chamber 1024 may have a width which is greater than that ofthe metering chamber 146. Capillary forces may be used then to keep thefluid in the metering chamber 146. The dashed line labeled 1030 and alsoA-A shows the location of a cross-sectional view of the metering chamber112. The cross section A-A 1030 is equivalent to the cross section A-Ain FIG. 10. The details described with respect to FIG. 11 also apply tothe cross section A-A in FIG. 19.

The aliquoting chamber 144 can be shown as also having a vent 1028. Theregion around the duct entrance 1014 is in this embodimentfunnel-shaped. It may also be noted that the aliquoting chamber 144 isshown as not having sharp edges. The lack of sharp edges helps tofacilitate the movement of fluid from the aliquoting chamber 144 to theduct entrance 1014 when the disc is decelerated.

The aliquoting chamber 144 is also shown as having a connection to afluidic connection 1034 which leads to an excess fluid chamber 1032. Thefluidic connection 1034 has a fluidic connection entrance 1036. Thefluidic connection entrance 1036 defines the maximum fluid level in thealiquoting chamber 144. The maximum fluid level in the aliquotingchamber 144 is further from the rotational axis 102 than the duct exit1016. The fluidic connection 1034 is connected to the excess fluidchamber 1032 in this example. The use of a valve or a capillary valve isoptional. The excess fluid chamber is shown as having a vent 1028 and itis also connected to a fail-safe chamber 1040. When the fluid flows intothe excess fluid chamber 1032 the fail safe 1040 chamber is filled. Thefail safe chamber 1040 may be used to indicate optically if fluid hasentered the excess fluid chamber 1032. For example during use if thefail safe chamber 1040 is not filled it may indicate that the aliquotingchamber 144 was not properly filled with fluid.

FIGS. 20-26 illustrate how the metering structure 140′ may be used toperform multiple aliquotations of fluid to fluidic element 150.

First in FIG. 20 fluid has been added to the fluid chamber 136. Thecartridge is then spun about the rotational axis 102, which forces fluidor washing buffer 1202 to travel through the first duct 106 into thealiquoting chamber 144. The fluid 1202 then fills the aliquoting chamber144 and the corresponding radially outwards portion of the connectingduct 148 with fluid.

FIG. 21 shows the cartridge spinning at the same rate and same direction1200 as was shown in FIG. 20. In FIG. 21 all the fluid has been drainedout of the fluid chamber 136. The fluid 1202 can be shown as filling theconnecting duct 148 and the aliquoting chamber 144 to the maximum fluidlevel 1300 which is set by the fluid connection entrance 1036. Excessfluid 1202 can be shown as being filled into the excess fluid chamber1032 and the fail safe chamber 1040.

Next in FIG. 22 the disc stops or is decelerated to a lower rotationalfrequency. Capillary action in the connecting duct 148 and the meteringchamber 146 is shown as beginning to draw fluid into the meteringchamber 146. The fluid 1202 first fills the periphery or edge of themetering chamber 146. This is because of the tapered side walls 1104shown in FIG. 11. Capillary action causes the side wall portion of themetering chamber 146 to fill first. This helps preventing the formationor adhesion of bubbles within the metering chamber 146. When thecartridge is rapidly de-accelerated inertia of the fluid 1202 may alsohelp it to enter the metering chamber 146.

Next in FIG. 23 the cartridge is shown as being still stationary or at areduced rotation rate and the metering chamber 146 is completely filledwith fluid 1202. The cartridge or disc may still be considered to be atrest.

FIG. 24 shows the same view as is shown in FIG. 23 except a dashed line1600 has been drawn in the metering chamber 146. This line 1600 in themetering chamber 146 divides the fluid in the metering chamber intoseveral parts or portions. A part of the fluid volume or the whole fluidvolume 1604 radially inwards (closer to the rotational axis 102) fromthe line 1600 may flow back into the reservoir. The radially outwardspart (further away from the rotational axis 102) or part 1602 may betransferred into the fluidic element 150. The radially inward part 1604can be referred to as the remaining part of the fluid and the radiallyoutward part 1602 can be referred to as the part of the fluid 1602 thatis transferred into the fluidic elements 150. The volume of the fluid1602 is the aliquot.

Next in FIG. 25 the disc begins to accelerate and spin around in thedirection 1200. The disc accelerates; this causes the capillary valve1021 to open. The remaining part of the fluid 1604 was transferred backto the aliquoting chamber 144. The part of the fluid 1602 is in theprocess of being transferred to the downstream fluidic element 150. Adrop of the fluid 1202 can be seen dropping from the tube-like structure1020.

Next in FIG. 26 it can be seen that the fluid volume 1602 has beencompletely transferred to the fluidic elements 150 and is no longervisible in FIG. 26. The remaining part of the fluid 1604 has beentransferred back into the aliquoting chamber 144 and is mixed with theremaining fluid 1202. The first aliquotation step is finished; theprocess may be repeated again from FIG. 22 and may be repeated until thefluid volume 1202 in the aliquoting chamber 144 is smaller than thevolume of the metering chamber 146.

LIST OF REFERENCE NUMERALS

-   -   100 cartridge    -   102 rotational axis    -   104 circular outer edge    -   106 flat outer edge    -   108 blood inlet    -   110 storage chamber    -   112 expansion chamber    -   112′ expansion chamber    -   114 vent    -   116 failsafe indicators    -   118 blood separation chamber    -   120 overflow chamber    -   122 first valve structure    -   124 processing chamber    -   126 surface for reagent    -   128 second valve structure    -   130 measurement structure    -   132 absorbent structure    -   134 chromatographic membrane    -   136 fluid chamber    -   136′ fluid chamber    -   138 fluid duct    -   138′ fluid duct    -   140 metering structure    -   140′ metering structure    -   142 manual fill location    -   144 aliquoting chamber    -   146 metering chamber    -   148 connecting duct    -   150 fluidic element    -   300 upper portion    -   302 lower portion    -   304 overflow opening    -   306 siphon entrance    -   308 siphon exit    -   310 nearest location    -   400 valve element    -   402 valve element    -   500 first sub chamber    -   502 second sub chamber    -   504 intermediate valve structure    -   600 blood    -   602 analyte in blood    -   602′ analyte in plasma    -   604 plasma generation    -   606 mixing plasma with dried assay reagents and incubation in        processing chamber    -   608 capture antibody    -   609 transport to measurement structure    -   610 detection antibody    -   611 analyte specific binding partner complex.    -   612 motion of plasma across membrane    -   614 capture and detection zone    -   616 instrument control zone    -   618 assay control zone    -   620 capture element    -   622 artificial analyte line    -   700 medical system    -   702 cartridge spinner    -   704 motor    -   706 gripper    -   708 portion of cartridge    -   710 measurement structure    -   711 actuator    -   712 optical measurement system    -   714 controller    -   716 hardware interface    -   718 processor    -   720 electronic storage    -   722 electronic memory    -   724 network interface    -   726 network connection    -   728 laboratory information system    -   730 executable instructions    -   732 measurement    -   800 rotating the cartridge about the rotational axis to        transport the blood sample into the blood separation chamber    -   802 controlling the rotation of the cartridge about the        rotational axis to separate the blood plasma from the        corpuscular blood sample components by centrifugation    -   804 opening the first valve structure and rotating the cartridge        about the rotational axis to transport a defined portion of the        blood plasma from the blood separation chamber to the processing        chamber    -   806 holding the portion of the blood plasma in the processing        chamber    -   808 releasing the seal to enable a first part of the washing        buffer to enter the measurement structure    -   810 opening the second valve structure to transfer the at least        one specific binding partner complex to the measurement        structure and controlling the rotational rate of the cartridge        to allow the at least one analyte specific binding partner        complex to flow to the measurement structure through the second        valve structure    -   812 controlling the rotational rate of the cartridge to allow        the at least one analyte specific binding partner complex to        flow across the membrane to the absorbent structure at a defined        velocity and to allow the at least one analyte specific binding        partner complex to bind to the immobilized binding partner    -   814 controlling the rotational rate of the cartridge to allow        the first part of the washing buffer to flow across the membrane        to the absorbent structure at a defined velocity    -   816 performing the measurement using the membrane and using an        optical measurement system for the analyte quantization    -   900 cartridge in initial condition    -   902 place blood into inlet    -   904 transfer of sample to blood separation chamber    -   906 plasma separation by centrifugation    -   908 transfer blood plasma to processing chamber    -   910 mix blood plasma with reagent    -   912 release of wash buffer    -   914 transfer incubate to measurement structure    -   916 chromatography of analyte specific binding partner complex    -   918 metering of wash buffer    -   920 transfer of wash buffer    -   922 chromatography of wash buffer    -   924 measurement of analyte    -   1014 duct entrance    -   1016 duct exit    -   1018 circular arc    -   1020 tube-like structure    -   1021 valve    -   1024 expansion chamber    -   1026 upper edge    -   1028 vent    -   1030 profile A-A    -   1032 excess fluid chamber    -   1034 fluidic connection    -   1036 fluidic connection entrance    -   1038 capillary valve    -   1040 fail safe chamber    -   1100 cross sectional view A-A    -   1102 body of cartridge    -   1104 side walls    -   1106 central region    -   1108 lid    -   1110 support structure    -   1200 direction of rotation    -   1202 fluid    -   1300 maximum fluid level    -   1600 dividing line    -   1602 part of fluid    -   1604 remaining part of fluid

What is claimed is:
 1. A medical system comprising: a cartridge operablefor being spun around a rotational axis, wherein the cartridgecomprises: an inlet for receiving a blood sample; a blood separationchamber for separating blood plasma from the blood sample, wherein theblood separation chamber is fluidically connected to the inlet; aprocessing chamber containing at least one reagent comprising at leastone specific binding partner which is operable to bind to an analyte toform at least one analyte specific binding partner complex; a firstvalve structure connecting the blood separation chamber to theprocessing chamber; a measurement structure for enabling measurement ofthe quantity of the analyte, wherein the measurement structure comprisesa chromatographic membrane, wherein the chromatographic membranecomprises an immobilized binding partner for direct or indirect bindingof the analyte or the at least one analyte specific binding partnercomplex, wherein the measurement structure further comprises anabsorbent structure, wherein the absorbent structure is nearer to therotational axis than the membrane; a second valve structure connectingthe processing chamber to the measurement structure; a fluid chamberfilled with a washing buffer, wherein the fluid chamber is fluidicallyconnected to the measurement structure, wherein a seal keeps the washingbuffer within the fluid chamber; an aliquoting chamber for aliquotingand/or supplying aliquots of the washing buffer received from the fluidchamber; a fluid duct connecting the fluid chamber with the aliquotingchamber; a metering chamber; a connecting duct which fluidicallyconnects the metering chamber with the aliquoting chamber, wherein themeasurement structure is connected to the metering chamber via fluidicelements; and a vent connected to the metering chamber, wherein the ventis nearer to the rotational axis than the metering chamber.
 2. Themedical system of claim 1, wherein the metering chamber has side wallsand a central region, wherein the side walls taper away from the centralregion, and wherein capillary action next to the side walls of themetering chamber is greater than in the central region of the meteringchamber.
 3. The medical system of claim 1, wherein the metering chamberis operable for causing fluid to fill the metering chamber usingcapillary action, wherein the connecting duct comprises a duct entrancein the aliquoting chamber, wherein the connecting duct further comprisesa duct exit in the metering chamber, wherein the duct exit is closer tothe rotational axis than the duct entrance, and wherein the connectingduct is operable for causing fluid to flow to the metering chamber usingcapillary action.
 4. The medical system of claim 1, wherein theconnecting duct comprises a duct entrance in the aliquoting chamber,wherein the connecting duct further comprises a duct exit in themetering chamber, and wherein a circular arc about the rotational axispasses through both the duct entrance and the duct exit.
 5. The medicalsystem of claim 1, wherein the first valve structure is a first siphon,wherein the cartridge further comprises an overflow chamber connected tothe blood separation chamber, wherein the overflow chamber comprises anopening, wherein the first siphon comprises a siphon entrance in theblood separation chamber, wherein the first siphon comprises a siphonexit in the processing chamber, wherein the opening is closer to therotational axis than the siphon exit, wherein the siphon exit is closerto the rotational axis than the siphon entrance.
 6. The medical systemof claim 1, wherein the processing chamber comprises at least two subprocessing chambers, wherein each of the at least two sub processingchambers are fluidically connected by an intermediate valve structure,wherein the processing chamber contains two or more reagents, whereineach of the at least two sub processing chambers contains a portion ofthe two or more reagents.
 7. The medical system of claim 1, wherein themedical system further comprises an cartridge spinner for controllingrotation of the cartridge about the rotational axis, wherein the medicalsystem further comprises a memory for storing machine executableinstructions and a processor for controlling the medical system, whereinexecution of the machine executable instructions causes the processorto: rotate the cartridge about the rotational axis to transport theblood sample into the blood separation chamber by controlling thecartridge spinner; control the rotation of the cartridge about therotational axis to separate the blood plasma from the corpuscular bloodsample components by centrifugation by controlling the cartridgespinner; open the first valve structure and rotating the cartridge aboutthe rotational axis to transport a defined portion of the blood plasmafrom the blood separation chamber to the processing chamber at leastpartially by controlling the cartridge spinner; hold the portion of theblood plasma in the processing chamber by controlling the cartridgespinner, wherein the blood plasma mixes with the reagent and combineswith the at least one specific binding partner to form the at least oneanalyte specific binding partner complex; release the seal to enable afirst part of the washing buffer to enter the measurement structure;open the second valve structure to transfer the at least one analytespecific binding partner complex to the measurement structure andcontrolling the rotational rate of the cartridge to allow the at leastone analyte specific binding partner complex to flow to the measurementstructure through the second valve structure at least partially bycontrolling the cartridge spinner; control the rotational rate of thecartridge to allow the at least one analyte specific binding partnercomplex to flow across the membrane to the absorbent structure at adefined velocity and to allow the at least one analyte specific bindingpartner complex to bind to the immobilized binding partner bycontrolling the cartridge spinner; control the rotational rate of thecartridge to allow the first part of the washing buffer to flow acrossthe membrane to the absorbent structure at a defined velocity bycontrolling the cartridge spinner; and measure a quantity of the analyteusing the membrane and by controlling an optical measurement system. 8.The medical system of claim 7, wherein the medical system furthercomprises a seal opener, wherein execution of the machine executableinstructions causes the processor to control the seal opener to: releasethe seal to enable the washing buffer to enter the aliquoting chamberbefore decrease the rotational rate of the cartridge to permit thewashing buffer in the aliquoting chamber to transfer into the connectingduct and to fill the metering chamber a first time.
 9. The medicalsystem of claim 7 wherein the medical system further comprises anoptical measurement system for performing the measurement using thechromatographic membrane.
 10. The medical system of claim 1, wherein themedical system further comprises a temperature controller formaintaining the temperature of the cartridge within a predeterminedtemperature range.
 11. The medical system of claim 2, wherein theconnecting duct comprises a duct entrance in the aliquoting chamber,wherein the connecting duct further comprises a duct exit in themetering chamber, and wherein a circular arc about the rotational axispasses through both the duct entrance and the duct exit.
 12. The medicalsystem of claim 2, wherein the first valve structure is a first siphon,wherein the cartridge further comprises an overflow chamber connected tothe blood separation chamber, wherein the overflow chamber comprises anopening, wherein the first siphon comprises a siphon entrance in theblood separation chamber, wherein the first siphon comprises a siphonexit in the processing chamber, wherein the opening is closer to therotational axis than the siphon exit, wherein the siphon exit is closerto the rotational axis than the siphon entrance.
 13. The medical systemof claim 2, wherein the processing chamber comprises at least two subprocessing chambers, wherein each of the at least two sub processingchambers are fluidically connected by an intermediate valve structure,wherein the processing chamber contains two or more reagents, whereineach of the at least two sub processing chambers contains a portion ofthe two or more reagents.
 14. The medical system of claim 9, wherein themedical system further comprises a seal opener, wherein execution of themachine executable instructions causes the processor to control the sealopener to: release the seal to enable the washing buffer to enter thealiquoting chamber before decrease the rotational rate of the cartridgeto permit the washing buffer in the aliquoting chamber to transfer intothe connecting duct and to fill the metering chamber a first time. 15.The medical system of claim 14, wherein the medical system furthercomprises a temperature controller for maintaining the temperature ofthe cartridge within a predetermined temperature range.